Expanding Hybrids And The Rise Of Our Genetic Common Denominator

With the attestation of Neanderthal and Denisova DNA in the human genome, and strong indications for the genetic contribution of also other archaic hominines previously considered ‘extinct without issue’, the simple model of prefabricated, homogenous modern humans that moved ‘out-of-Africa’ to replace the human evolutionary residue all over the world in a single blow, failed dramatically. Now, the scientific community is literally forced to pay attention to decades of accumulated counter-evidence and criticism.

Average Joe replacing Average Joe: A new genetic common denominator rises up from the earth, combining the best of all available biological elements to adapt to a new way of life. Average Joe is a Hybrid!

One issue concerns the implied range expansions of a single ‘bottlenecked’, homogenous population that extended its African habitat to entirely new environments and climates. This should have been attested by selective sweeps in the genome – but it doesn’t.

While most people assumed that the out-of-Africa expansion had been characterized by a series of adaptations to new environments leading to recurrent selective sweeps, our genome actually contains little trace of recent complete sweeps and the genetic differentiation of human population has been very progressive over time, probably without major adaptive episodes.
[…] if some introgressed genes were really advantageous, they should have spread and fixed in the human population, but […] there is no widespread signature of strong selective sweeps in Eurasia. (Alves et al., 2012)

Selective sweep can be recognized by a large reduction of genetic variation near a favorable gene on the chromosome, caused by a quick expansion within a population of the gene by natural selection. Only a few complete sweeps and near-complete sweeps could be found, ‘suggesting that there was relatively little directional adaptive evolution associated with the “origin of modern humans.” Measuring by genetic change, agriculture was many times more important than the appearance of modern humans throughout the world’ (Hawks, 2012-07-20). Does this imply that genetic change of modern humans was predominantly not the result of sudden adaptive mutations? Possibly humans acquired their genetic adaptations to their respective extant environments in a different way:

[…] there are precious few genetic changes shared by all (or even most) humans today, that are not also shared with Neandertals, Denisovans, or plausible other archaic human groups (such as archaic Africans).
That of course follows from the fact that a fraction of today’s gene pool actually comes from those ancient groups. Their variation is (by and large) human variation. (Hawks, 2012-07-20)

Apparently, there was a host of archaic hominines out there, previously considered the evolutionary ‘dead ends’ from all over the world, whose traces can still be perceived as superimposed variability in the modern human genome. That is, up to now investigation on archaic admixture is mainly focused on the differences between modern populations, that increasingly emerge as the relicts of intense ‘archaic’ hybridization processes. ‘Neandertals and Denisovans fall within the variation observed for human nuclear sequences. Thus, only few fixed differences can be identified’ (Meyer et al., 2012). This way, out of 3.2 billion sequenced Neanderthal base pairs only about 600 Mb could be unambiguously attributed to Neanderthal introgression, what is low in comparison with Meyer’s estimation that 6.0% of the genomes of present-day Papuans derive from Denisovans. But, archaic hominines also shared a considerable genetic common denominator with modern humans, whose possible incorporation remains poorly analyzed. A variable portion of archaic DNA actually being shared with modern humans could affect the observed magnitude of introgression, but earlier assertions that Denisovans were indeed more divergent were never confirmed. Without clear traces of selective sweep, the true origin of ambiguously shared and distinctly archaic portions of the genome are impossible to tell apart. Reported examples of selective sweep remain rare:

We also identify over 100 Neandertal-derived alleles that are likely to have been the target of selection since introgression. One of these has a frequency of about 85% in Europe and overlaps CLOCK, a key gene in Circadian function in mammals. This gene has been found in other selection scans in Eurasian populations, but has never before been linked to Neandertal gene flow. (Sankararaman et al., 2012)

The circadian function refers to a chrono-biological adjustment to an external rhythm like daylight, what logically implies a genetic adaptation to the northern Neanderthal habitat with an exclusive advantage for northern populations. Such an introgressed innovation that apparently behaves like a new favorable mutation remains an exception, since hybrid incorporation and repatterning of whole chunks of introgressed DNA doesn’t require selective sweep.

These days many investigators try to reconstruct the past demography in their own way, though often the effort remains haunted by some remarkably conservative out-of-Africa assumptions. A wealth of newly published information on the subject is currently waiting for a proper interpretation to close the gap between our modern genome and the sequenced data retrieved from some of our ancestors. Conflicting perspectives often result in contradictory assertions that may be counter-intuitive and in need of reconciliation one with the other. The following investigation belongs to this category:

We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30X) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity, indicating that genetic diversity in these archaic hominines was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.

This study has several interesting results worth mentioning: an extremely low genetic diversity of Denisova humans that can’t be observed in any modern population; the observation that Europeans have 24% less Neanderthal admixtures (“not being shared by Africans”) than Asians; and apparent indications of some hybridization event in the past, still noticeable in the chromosomes of all modern Denisovan descendents.

Low genetic diversity of Denisovans puts the asserted homogeneity of the modern human species in a new perspective. Despite all earlier speculation on an African bottleneck, designed to explain modern genetic homogeneity from a phylogenetic perspective, current genetic variability is now found to exceed the attested variability of ancient Denisovans for all modern ‘phyles’, or ethnicities:

Several methods indicate that the Denisovan hetero-zygosity is about 0.022%. This is ~20% of the heterozygosity seen in the Africans, ~26–33% of that in the Eurasians, and 36% of that in the Karitiana, a South American population with extremely low heterozygosity. Since we find no evidence for unusually long stretches of homozygosity in the Denisovan genome, this is not due to inbreeding among the immediate ancestors of the Denisovan individual. We thus conclude that genetic diversity of the population to which the Denisovan individual belonged was very low compared to present-day humans. (Meyer et al., 2012)

Nevertheless, Denisovans lack any relevant African affiliation. Their ‘phyle’ should have been separated long enough from the other branches of human evolution to have reached a genetic diversity comparable to Africans. Apparently, since this didn’t happen, genetic variability doesn’t simply translate to the age of an otherwise isolated population. Investigators may now dedicate their diligence to duplicate their calculations for a purported recent African bottleneck, and design a corresponding recent Denisovan bottleneck. Or they could just admit the geographic maxima of modern variability in Africa may rather represent archaic admixture than the age of a single human phyle.
Unfortunately, the Meyer study doesn’t mention the Neanderthal-like admixtures of Africans, except by saying that the ‘genetic contribution from Neandertal to the present-day human gene pool is present in all populations outside Africa’. It is important to keep this voluntary restriction in mind in reading their most remarkable assertion: ‘We estimate that the proportion of Neandertal ancestry in Europe is 24% lower than in eastern Asia and South America’ (Meyer et al., 2012).
This runs contrary to more detailed genetic analyses that previously revealed slightly higher levels of Neanderthal admixture in Europe. John Hawks counted derived SNP alleles of the 1000 Genomes Project being shared with the (Neanderthal) Vindija Vi33.16 genome, and found the surpluses in Europe and East Asia where rather comparable:

The Europeans average a bit more Neandertal than Asians. The within-population differences between individuals are large, and constitute noise as far as our comparisons between populations are concerned. At present, we can take as a hypothesis that Europeans have more Neandertal ancestry than Asians. If this is true, we can further guess that Europeans may have mixed with Neandertals as they moved into Europe, constituting a second process of population mixture beyond that shared by European and Asian ancestors. (Hawks, 2012-02-08 )

Unfortunately, the attested agreement between non-African and Neandertal genomes, and between Melanesian and Denisova genomes for that matter, didn’t result yet in the full identification of all specific genetic loci involved. Basically, the observed agreement was initially based on the differences between Africans and non-Africans in comparison with the archaic genome being investigated. Hence, the overall picture of archaic ‘differences’ may be distorted by shared components within the African reference group, that Meyer’s team didn’t include in their investigation and that Hawks didn’t quantify for his modern genomes that share derived SNP alleles with the (Neanderthal) Vindija Vi33.16 genome. In other words, this Neanderthal ancestry in Europe allegedly being 24% lower than Asia (according to Meyer et al.) is essentially meaningless without additional information that quantifies sharing:

My initial reaction to this difference is that it reflects the sharing of Neandertal genes in Africa. Meyer and colleagues filtered out alleles found in Africa, as a way of decreasing the effect of incomplete lineage sorting compared to introgression in their comparison. But if Africans have some gene flow from Neandertals, eliminating alleles found in Africans will create a bias in the comparison. If (as we think) some African populations have Neandertal gene flow, that probably came from West Asia or southern Europe. So as long as the present European and Asian (and Native American) samples have undergone a history of genetic drift, or if (as mentioned in the quote) they mixed with slightly different Neandertal populations, this bias will tend to make Asians look more Neandertal and Europeans less so.
Anyway, this demands further investigation. (Hawks, 2012-08-30)

Apparently, the legacy of the Out-of-Africa dogma caused Meyer et al. to take the African part for granted and just to look at the non-African part. We are lucky to have some additional information already at hand to more or less visualize how the Meyer et al. results could still be in tune with earlier results, that rather emphasized a closer match of Neanderthal admixtures with Europeans. The Austrian study of Hochreiter et al. (2012) actively incorporates the internationally shared Neanderthal and Denisova alleles in their calculations to measure the probability of uneven distribution (Fisher’s exact test) and to obtain the corresponding odds ratios, that give a symmetrical representation of the relative genetic enrichment for each type of admixture. From here on, all depends on how we perceive the human genome and what part of it we are willing to recognize as true Neanderthal or Denisova admixture, or something else.
Hochreiter’s study retrieved data from the Korean Personal Genome Project (KPGP) combined with those from the 1000-Genomes-Project:

Genotyping […] 1,131 individuals and 3.1 million single nucleotide variants (SNVs) on chromosome 1 […] identified 113,963 different rare haplotype clusters marked by tagSNVs that have a minor allele frequency of 5% or less. The rare haplotype clusters comprise 680,904 SNVs; that is 36.1% of the rare variants and 21.5% of all variants. The vast majority of 107,473 haplotype clusters contains Africans, while only 9,554 and 6,933 contain Europeans and Asians, respectively. (Hochreiter et al., 2012)

According to this data, only 6,490 (113,963 minus 107,473) of the rare haplotype clusters on chromosome 1 were exclusively non-African. The vast majority of all rare haplotypes, however, are shared with Africans one way or the other:

We characterized haplotypes by matching with archaic genomes. Haplotypes that match the Denisova or the Neandertal genome are significantly more often observed in Asians and Europeans. Interestingly, haplotypes matching the Denisova or the Neandertal genome are also found, in some cases exclusively, in Africans. Our findings indicate that the majority of rare haplotypes from chromosome 1 are ancient and are from times before humans migrated out of Africa. (Hochreiter et al., 2012)

The 9,554 and 6,933 European and Asian haplotypes thus per definition include a considerable overlap with extant African rare haplotypes. Moreover, the size of such an African overlap is proportional with the total count of shared Eurasian haplotypes. Mathematically it could be deduced that at the very least, 3,064 (ie. 9,554 minus 6,490) out of 9,554 ‘European’ haplotypes, and 443 out of 6,933 ‘Asian’ haplotypes should be also African. The maximum count of African rare haplotypes, however, that made it ‘Out-of Africa’ and are currently shared with non-Africans, remained well below 10%. Since over 90% of the African rare haplotypes are thus not shared with Neanderthals and Denisovans, in an Out-of-Africa scenario this would mean that a similar proportion of the European and Asian rare haplotypes could be expected to be non-Neanderthal and non-Denisova. Could we really rely on the ancestral origin of so many shared haplotypes? Just being shared African doesn’t make these haplotypes ancestral all of a sudden, and less without a proper quantification.
Let’s first try to quantify the potential Neanderthal admixtures a bit. Hu’s analyses of archaic segments should give an adequate peek inside the various admixtures for an educated guess:

Archaic hominin admixture with modern non-Africans was detected by genome wide analysis of Neanderthal and Denisovan individuals.
[…]
To gain better understanding in demographic and evolutionary significance of archaic hominin admixture, […] we identified 410,683 archaic segments in 909 non-African individuals with averaged segment length 83,460bp. In the genealogy of each archaic segment with Neanderthal, Denisovan, African and chimpanzee segments, 77~81% archaic segment coalesced first with Neanderthal, 4~8% coalesced first with Denisovan, and 14% coalesced first with neither (Hu et al., 2012)

Considering the above, apparently very few (or none?) of all the non-archaic haplotypes that made it out of Africa became rare. Such results, naturally, would imply one enormous problem about the construct Homo Sapiens Sapiens (HSS). Instead, the lack of rare haplotypes outside Africa that could be safely assigned unambiguously to what is generally considered the constituent forerunner of modern humans, indeed echoes much earlier claims of ancestral homogeneity. As already referred to above, population geneticist are very much acquainted with the concept of an early HSS bottleneck, since this was once designed to explain away all evidence of this kind. Hence, I appreciate the reasons why Hochreiter et al. prefer to consider the rare Denisova- and Neanderthal-like rare haplotypes in Africa ‘ancestral’, even those being exclusively African, but this preposition logically implies the existence of allegedly HSS ancestral haplotypes in Eurasia that are neither rare nor absent in Neanderthal and Denisova. Combined with the ever more unpopperian association of frequent haplotypes with HSS per definition, it has now all appearance Homo Sapiens Sapiens is nothing but the current genetic common denominator in disguise.
As for now, apparently the Neanderthal admixtures indeed account for the greater part of the Eurasian archaic components. The discovery of the Denisova component was just mere luck, and the odds are high that more archaic hominines contributed to the Eurasian admixtures. For all we know, on the eve of the transition to modern humans Europe was only inhabited by Neanderthal. However, the likelihood of additional archaic admixture in South East Asia are being widely discussed. Moreover, Hu’s results almost exclude the possibility that substantial African archaic admixtures, at least those not yet being fully incorporated in the ‘bottlenecked’ HSS population, expanded out of Africa. Altogether, it wouldn’t be farfetched to consider most of the 14% Eurasian remainder to be essentially archaic Asian. Actually, Hu’s 14% Eurasian admixtures currently unaccounted for could easily correspond to the genetic contribution of up to four Asian archaic hominines like Denisovan’s – wherever those may have existed in isolation from Denisovan-like populations that – as for now – potentially inhabited the large geographic stretch between their attested remains in the Altai mountains and their attested genetic contributions in Melanesia. Mendez et al. (2012) suggested ‘that the archaic ancestor contributing the deep lineage to Melanesians and the specimen from Denisova were members of genetically differentiated populations’, what indeed should make us wonder about the Asian location, or nature, of such unsampled hominine groups we are still missing from the record of potential archaic admixtures. Even locally admixted homo erectus have already been proposed.
Now, Hu’s fixed non-Neanderthal-non-Denisovan remainder and the ambiguous 4% apparently shared component between both sampled hominines, suggest ~40-50% ancestral overlap between Neanderthals and Denisovans for the admixtures attributed to Denisovans, against only ~4-5% ancestral overlap for Neanderthal-like admixtures. The unambiguous Denisovan component left may be considered fully Asian in origin, even though Meyer et al report an opposite effect on the current availability of Denisovan alleles all over the world:

Interestingly, we find that Denisovans share more alleles with the three populations from eastern Asia and South America (Dai, Han, and Karitiana) than with the two European populations (French and Sardinian) (Z = 5.3). However, this does not appear to be due to Denisovan gene flow into the ancestors of present-day Asians, since the excess archaic material is more closely related to Neandertals than to Denisovans (Meyer et al., 2012)

Indeed, the contribution from Denisovans is found ‘almost’ exclusively in island Southeast Asia and Oceania. Hence, Meyer’s assumption this effect is directly related to a higher proportion of archaic Neanderthal alleles in Asia justifies a ‘worse case’ scenario, where the ‘true’ Asian share could probably increase to 18-19%, against up to 81% rare archaic haplotypes that could now be tentatively attributed to essentially Eurasian Neanderthal admixtures. For now we are only interested in the counts of Neanderthal-like admixtures, so we could propose a conversion of Hochreiter’s rare haplotype counts results, that reduces the non-African count of rare haplotypes to ~5,224 Neanderthal non-African haplotypes, and that reduces the ‘non-exclusive Asian’ haplotypes to ~5,581 Neanderthal non-exclusive Asian haplotypes, while the same maximum of Hochreiter’s 9,554 haplotypes could still be assumed to be both ‘Neanderthal’ and ‘non-exclusive European’.
For sure, such an increased proportion for Neanderthal-like admixtures in Europe doesn’t make Meyer’s results more intuitive. All the contrary, Meyer’s 24% lower European contribution should make us wonder where the differences went to. Apparently, a changed proportion of non-African Neanderthal-like admixtures in Europe compared to Asia needs proportional compensation elsewhere. Unfortunately, this effect has not been illustrated in any of the studies that aim to quantify Neanderthal admixtures one way or the other.

Different scenarios based on Hochreiter’s rare haplotypes, Hu’s proportions of archaic contribution, and the following viable assumptions: Zero Eurasian and Afro-Asian components for scenario #1; Zero Eurasian and Afro-Eurasian components for scenario #2; Zero European and Afro-Eurasian components for scenario #7. The Meyer-scenarios assume a 24% lower non-African European component than Asian, while #1 and #2 were also calculated for equal shares. Lower Neanderthal-like proportions for Europe in comparison with Asian apparently imply a higher count for shared Afro-European haplotypes. The invariable high Afro-European component and less relevant Eurasian, Afro-Asian and Afro-European components are in support of an underpinning Eurasian substructure for the Neanderthal admixed population; and a massive expansion of already admixed European populations into Africa.

For a better comprehension I elaborated several possible solutions, combining the information of Hochreiter, Meyer and Hu. Hochreiter supplied values for three linear equations that involve six variables, representing the rare haplotype counts characterized as ‘exclusive European’, ‘exclusive Asian’, ‘Eurasian’, ‘Afro-Asian’, ‘Afro-European’ and ‘Afro-Eurasian’ . Meyer’s published proportion between European and Asian haplotypes introduces a fourth equation, that for comparison could be alternated with a more intuitive scenario that has non-African European and Asian rare haplotypes evenly distributed. However, a set of linear equations may only be solved (but not necessarily) if the number of equations is the same as the number of variables. Thus two variables remain undefined, what means that an array of solutions is still possible. I worked out a number of different scenarios, each based on two additional assumptions that are necessary to solve the equations. Thus, for scenario #1 I choose zero values for the Eurasian and Afro-Asian components; for scenario #2 I choose zero values for the Eurasian and Afro-Eurasian components; for scenario #3 I kept the Eurasian and Afro-European components on zero; for scenario #4 the same for the Afro-Asian and Afro-Eurasian components; for scenario #5 the Afro-European and Afro-Eurasian components were kept zero; for scenario #6 the same for the Afro-European and Afro-Asian components; and for scenario #7 zero values were assumed for the Afro-Eurasian and European component, the latter being valid only for the Meyer variant of the equations.
Scenarios #3-5 can’t be solved for natural values and scenario #6 is ambiguous. The remaining scenarios #1, #2 and #7 all show the predominance of shared Afro-European rare haplotypes, while Afro-Asian, Eurasian and Afro-Eurasian components are lower and not always required for a valid result. The effect of Meyer’s result can be illustrated for scenarios #1 and #2, where lower Neanderthal-like proportions for Europe in comparison with Asian apparently imply a higher count for shared Afro-European haplotypes and lower counts for Afro-Asian and Afro-Eurasian haplotypes.
These scenarios reveal the Afro-Asian component as fairly irrelevant, and the Afro-Eurasian component emerges as moderately weak. Only the Afro-European component remains definitely prominent in all scenarios. Remarkably, simulations that increase the Eurasian shared component are directly proportional to increases of the Afro-European component, while both are inversely proportional to the Afro-Eurasian component. This behavior supports the hypotheses that the Afro-Eurasian shared component is only moderately present; that at least the Asian Neanderthal admixtures don’t share any African origin or association in particular; and that Neanderthal haplotypes rather seem to have expanded proportionally into Africa and Asia alike from a European center. Especially the increased Afro-European component is remarkable, since an ancestral origin results problematic for rare haplogroups that feature a structural deficit in Asia.
At this stage it is impossible altogether to distinguish between haplotypes that introgressed through Neanderthal admixtures and those that may be ‘safely’ regarded ancestral to both Neanderthal and modern humans – so we should refrain from doing so beforehand. How ancestral the shared African haplotypes could possibly be? African substructure is no longer viable as a major explanation of Neanderthal admixtures in Eurasia. Actually, African substructure was already contradictory with the earlier Out-of-Africa bottleneck-and-homogeneity paradigms, and an additional west-to-east substructure to explain essentially different admixture patterns for Europe and Asia, is even less conceivable. Instead, ‘recent admixture with Neanderthals accounts for the greater similarity of Neanderthals to non-Africans than Africans’ (Yang et al., 2012). Less exclusive scenarios, that allow for early admixture events in the ancient Near Eastern contact zone, aren’t any less problematic for the discrepancy and leave the much lower Afro-Asian component without explanation. The most progressive and intuitive Out-of-Africa scenario, that considers the predominantly European distribution of Neanderthal haplotypes and predicts an increased admixture rate in Europe, now results falsified by this closer examination of Meyer’s 24% lower European rate. Apparently, the current distribution of admixtures only appeared to be in favor of any overall Out-of-Africa framework. The apparent lack of shared Afro-Asian haplotypes doesn’t indicate an African route for Asian admixtures, nor does the low count of shared Afro-Eurasian haplotypes advocate the importance of an ancestral component. Instead, an underpinning West-East dichotomy or Eurasian substructure already in place for the Neanderthal population before the attested admixture has already been proposed as a valid explanation:

Europeans and Asians could show distinct components of Neanderthal admixture if they had admixed with European and central Asian Neanderthals, respectively (Alves et al., 201)

The Afro-European shared haplotypes can’t be older than the long term genetic differentiation of Eurasian Neanderthals, what adds up to the already expounded rejection of African substructure in a recent Out-of-Africa scenario. A better explanation may be found in a massive expansion (or ‘backmigration’) of European populations into Africa, and a corresponding submersal of almost their full share of Neanderthal admixtures inside Africa subsequent to some late-Neanderthal admixture event.
Now the falsification of an important shared ancestral compenent in the African count of rare haplotypes becomes evident, Hochreiter’s data, reporting that ‘haplotypes matching the Denisova or the Neandertal genome are also found, in some cases exclusively, in Africans’, may be viewed in an entirely new perspective. If introgression of Denisovan admixtures was part of a rather ancient gene flow, albeit considerably younger than the Eurasian Neanderthal differentiation still noticeable in the strongly regionalized Neanderthal admixtures, some Denisovan alleles could have reached Africa contemporaneously with the ‘other’ archaic admixtures that arrived there through the European route, as displayed by the calculated haplotypes pattern above. Especially the world-wide distribution of shared Neanderthal-Denisova alleles raises some questions into this direction.
More detailed analysis on the immune gene OAS1, involved in ‘Denisovan’ introgression, revealed this gene was embedded in a very divergent string of DNA, referred at as the ‘deep lineage’ haplotype. Its divergence from all the other extant OAS1-related haplotypes was strong enough to exhibit the signature of archaic introgression, what means the haplotype ‘may have introgressed into the common ancestor of Denisova and Melanesians via admixture with an unsampled hominin group, such as Homo erectus’ (Mendez et al., 2012). The haplotype resembles the Denisovan haplotype ‘with the exception of one site (position 30504), at which the extant human carries the derived C and the Denisova specimen carries the ancestral T’, but even more striking is the current homogeneity of the deep lineage:

The attested Denisovan fossils in the Altai mountains had a slightly more ‘ancestral’ version of the gene, thus being different from the extant ‘deep lineage’. Actually, this unique signature boils down to a single hybridization event for this haplotype that involved one ancestral parent not unlike, but slightly different from the sampled specimen of Denisova Cave. Also Meyer’s observation that ‘Papuans share more alleles with the Denisovan genome on the autosomes than on the X chromosome’ and that eg. on chromosome 11 Denisovan ancestry is estimated to be lower in Papuans than in East Eurasians, corroborate to this hypothesis:

[…] there is significant variability in Denisovan ancestry proportion compared with the genome-wide average not just on chromosome X, but also on individual autosomes that have estimates that are also lower (or higher) than the genomewide average. (Meyer et al., 2012 sup)

Unfortunately, despite the negative evidence accumulated by Meyer et al. in their supplement against their own sex-biased modern population-history pet theories, their main article stopped short of dwelling on far more interesting factors such as hybrid chromosome repatterning that include ‘natural selection against hybrid incompatibility alleles, which are known to be concentrated on chromosome X’ and a marked uneven distribution of Denisovan ancestry also in the autosomes.

With hybrids, crossover events tend to compromise lineage specific regulatory regions on the chromosomes. Only favorable repatterning of the hybrid chromosomes results in viable offspring.

The disproportionate absence of Denisovan admixtures on the X chromosome virtually excludes a sex-biased demographic history in Oceania as an explanation and indeed, in their supplement Meyer et al. elaborated a potential rejection on logical grounds: also migrating males bring in their share of X chromosomes, so this way it can’t just disappear. A removal of Denisovan chromosome X by natural selection after the gene flow can be excluded as well: selection acting on genomic functional elements can be detected by its indirect effects on population diversity at linked neutral sites (McVickers et al., 2009), but Meyer’s team was right that they couldn’t establish that archaic ancestry was affected by the proximity to genes. However, natural selection against hybrid incompatibility alleles is still a poorly understood process – and especially if considered applicable just to the protein coding genes that constitute only about 3 percent of the human genome. This year the ENCODE Project Consortium confirmed actually over 80% of the genome to be involved in biochemical functions, in particular outside of the protein-coding regions. Genetic viability is most of all determined by the proper regulation of gene expression. Hence, much of the genome is considered constrained by biological constraints against evolutionary change. Of interest are the ‘large number of elements without mammalian constraint, between 17% and 90% for transcription-factor-binding regions as well as DHSs and FAIRE regions’ (Dunham et al., 2012), referring to regions linked to regulatory functions. But even here, the autors hold that depressed derived allele frequencies indicate ‘an appreciable proportion of the unconstrained elements are lineage-specific elements required for organismal function, consistent with long-standing views of recent evolution’.
It should be obvious that nature can’t expect much viable offspring from a fusion of gametes that brings together lineage specific regulatory regions in a random fashion. The deleterious effects of random hybrid recombination appear to be inversely proportional to chromosome crossover events during meiosis, that normally happens once for each generation. First generation hybrid offspring typically has enough directly inherited consistency of their regulatory regions on their genome left for being viable. But next generation chromosome crossover may already affect the regulatory processes of the haploid gametes being produced by meiosis. Initially, this seriously affects fertility and only the sheer scale of gamete production may compensate for the high probability of next-generation hybrid malfunction. This close relation between hybrid viability and a limited array of favorable crossover events, that shouldn’t compromise the regulatory functionality of the hybrid genome, apparently resulted also in a marked variability of ancestry proportions for each chromosome across the genome of Denisovan admixed populations.
For hybrids, selective processes are more efficient when directed at regulatory viability just before and during conception. Post-natal fitness, on the other hand, is most of all based on the ‘proven technology’ of coding genes whose selective advantage and usefulness were already attested in the parent species. Natural selection based on the success of coding genes thus may have been of less importance in recent hominine evolution than could be expected for the profound genetic change modern humans apparently went through. This detail can indeed be confirmed in the modern genome by the above mentioned lack of genetic sweep, despite important repatterning and recent genetic innovation due exactly to the occurrence of abundant hybridization in recent human evolution.
For the moment this issue should be considered isolated from the origin of the shared Neanderthal-Denisovan haplotypes, especially since this portion was already in place for the sampled Neanderthal and Denisovan specimen. Tentatively, this shared portion could be attributed to an earlier ‘bi-directional’ gene flow, leaving the specific Denisovan admixtures in Melanesia apparently to a subsequent hybridization event that only seems to have affected modern populations. The proposal above of a single hybridization event virtually excludes a scenario where the hybrid population could be considered firmly rooted in a local archaic population. Naturally, this runs counter to an array of earlier proposals that rather link Denisovan admixture events with a wide geographic range of Denisovan hominine presence between the Altai mountains and SE Asia (Reich); with different places during the migration of modern humans (Rasmussen); with distinct Denisovan admixture events in Oceanians and East Asians (Skoglund and Jakobsson); or with a process of continuous admixture where migration routes overlap with archaic hominine ranges (Currat and Excoffier).
However, a single late-Denisovan hybridization event doesn’t suffice as an exclusive scenario in the light of new evidence that posits Denisova Cave as a hotbed of Neanderthal contact. Abundant remains of Neanderthal were found nearby the cave:

The Chagyrskaya 6 mandible […] allows us now to link this material morphologically as well to the Neanderthals in Western Eurasia. Several questions remain: the timing and extent of Neanderthal expansion into the Altai, and especially the potential coexistence and interaction between Neanderthals and Denisovans. Based on availabe dates, the Neanderthals in Okladnikov cave and the possibly slightly earlier Chagyrskaya remains overlap with the wide range of dates for Layer 11 of Denisova cave. (Viola et al., 2012)

Both species even shared the same cave:

we have determined a high-quality nuclear genome from a pedal phalanx found in Denisova Cave in 2010. We show that the pedal phalanx derived from a Neandertal and thus that Neandertals as well as Denisovans have been present in the cave. (Sawyer et al., 2012)

Extensive contacts should at least have initiated a kind of fusion between the Neanderthal and Denisovan parent species into a single population where in time, due to multiple hybridization events, the variability of introgressed DNA would have been restored and integrated, into the Neanderthal genetic heritage and vice-versa. Hybrid repattering of admixed chromosomes probably wouldn’t have raised Denisovan heterozygosity beyond the elevated levels observed in modern populations, and less given the outstanding native homozygosity of the sampled Denisovans as a starting point. Indeed, the Denisovan sample has a reduced heterozygosity compared to any of the present-day humans analyzed by Meyer et al, though they reported the relative ratios of heterozygosity as fairly constant, what could be considered problematic for the assumption of archaic Neanderthal admixture already present in the shared DNA with Denisovans. However, 29 coding CCDS genes could be identified with more than one fixed non-synonymous SNC where ‘Denisova’ carries the ancestral allele, while in eight of these (OR2H1, MUC17, TNFRSF10D, MUC6, MUC5B, OR4A16, OR9G1, ERCC5), the Denisovan individual appeared heterozygous for all SNCs present in the gene. In table S44 it can be verified that 37% of this heterozygosity can be found in chromosome 11, 13% in chromosomes 6 and 7, and 11% in chromosome 8, while eleven chromosomes are homozygous for all investigated genes. Though Meyer’s team proposes this to be the result of duplications or repetitive regions, this heteromorph signature basically leaves the possibility of hybridization more than open. Since this results focus on the fixed non-synonymous SNC where Denisova carries the ancestral allele and modern humans the derived allele, the documented non-ancestral polymorphisms of Denisova even resemble modern-like admixtures.
According to Dienekes, within the group of polymorphic Eurasian SNPs there are less Denisovan than Neanderthal SNPs that are also monomorphic in the African Mbuti Pygmys. Because, actually the relation between Denisovans and Pygmy is ancestral and they share ancestral SNPs. This might reflect a lower penetration into Africa of the shared Denisovan-Neanderthal portion of archaic admixtures. If so, this could be partly due to a Denisovan origin of this shared portion, though some degree of Eurasian Neanderthal substructure may be involved as well. Interestingly, this also implies the tentative modern-like part of potentially admixtured (ie. polymorphic) SNPs in the Denisovan genome is actually less ‘African’ than the Out-of-Africa hypothesis should be happy with. If anything, despite some modern-like features, those admixtures should be assumed of eastern Neanderthal origin.

Another modern-like feature of the potential Denisovan-Neanderthal hybridization is the above mentioned outstanding heterozygosity of chromosome 11, that almost screams for continuity with the hybrid signature of the same chromosome in Papuans, where Denisovan ancestry is strikingly low. I really wonder what could have been the impact of these hybrid changes for the now widespread Denisovan-like mtDNA segment inserted into this same chromosome 11 of modern human populations all over the world, as described in a previous post; and what could have been the link with the survival of insert-like mtDNA in the aboriginal DNA found in the Lake Mungo 3 remains (LM3) dated 40kya. But even a much lesser extend of any gradual continuation with respect to Denisova-related selective processes against hybrid incompatibility alleles would only make sense if modern populations are themselves the continuation of these same ancient hybridization processes. Apart from what this might imply for the very nature of the modern genome in general, we could at least incorporate this signature of a continuous hybridization process, that tentatively links the Altai Mountains with Oceania, in what we know about the current distribution of Denisovan admixtures. A northern route around the SE Asiatic habitat of probably very different archaic hominine populations, some of them possibly more erectus-like or even more habilis-like, such as Homo floresiensis (Argue et al., 2012), seems at present more likely than a straightforward direct southern route:

However, in contrast to a recent study proposing more allele sharing between Denisova and populations from southern China, such as the Dai, than with populations from northern China, such as the Han, we find less Denisovan allele sharing with the Dai than with the Han (Meyer et al., 2012)

Current evidence even seems to favor a specific Korean route before turning south along the Chinese coasts down to Oceania:

The enrichment of Neandertal haplotypes in Koreans (odds ratio 10.6 of Fisher’s exact test) is not as high as for Han Chinese from Beijing, Han Chinese from South, and Japanese (odds ratios 23.9, 19.1, 22.7 of Fisher’s exact test) – see also Figure 7. In contrast to these results, the enrichment of Denisova haplotypes in Koreans (odds ratio 36.7 of Fisher’s exact test) is is higher than for Han Chinese from Beijing, Han Chinese from South, and Japanese (odds ratios 7.6, 6.9, 7.0 of Fisher’s exact test) (hochreiter et al., 2012)

It has been suggested that ancient HLA-A genes of the primate immune system only survived on human chromosome 6 by balanced selection in the Denisovan lineage. Hence, the current geographical distribution of this genes is often taken as indicative for the wherabouts of Denisovan admixed descendents. As you can see on the attached map, the hybrid Denisovan trail described above corresponds fairly well with this view, except for Yunnan and Tibet where possible Denisovan-like admixtures are largely below detection level and certainly not derived from Melanesian arrivals. It can’t be excluded that here we may find the root origin of the archaic population whose remains were so far attested only in Denisova Cave. Interestingly, this hypothetized ultimate origin of the archaic Denisovan population is adjacent to Indo-China, where hominine evolution may have been as old and divergent as in Africa.
Thus, it becomes ever more difficult to identify with, or deny descendance of a particular hominine branch. Recent human evolution is like a snowball rolling down the hill. What we are is just everything what came down from the hill, and what didn’t stop rolling. We may question our ability to really take a turn since for all we know the ball just gathers more snow and increases momentum. We can’t even say our trail downhill was human all the way, or where it started, or define what sets the participants apart from everything else around it. But here we are, something completely new on the face of the earth. And most of it, we have in common.

If introgression of Denisovan admixtures was part of a rather ancient gene flow, albeit considerably younger than the Eurasian Neanderthal differentiation still noticeable in the strongly regionalized Neanderthal admixtures, some Denisovan alleles could have reached Africa contemporaneously with the ‘other’ archaic admixtures that arrived there through the European route, as displayed by the calculated haplotypes pattern above.

Now John Hawks stumbled upon the first finds of considerable Denisovan ancestry in Europe in his blog:

Another aspect of the Genographic results is an estimated proportion of Denisovan ancestry. This might seem a bit surprising, as for most participants in the project who lack Polynesian or Melanesian ancestry this proportion should be extremely low.
[…]
So I have been extraordinarily surprised to see that people are getting Geno2 results with up to 6% Denisovan ancestry!
What gives? None of my correspondents so far has anything other than European self-reported ancestry, making it seem very unlikely that have substantial Denisovan ancestry.
[…]
My preliminary assumption it that the result is spurious but I’ll try to figure out if there is a possibility of some Denisovan fraction beyond what has been shown in published work.

Spurious? On the contrary, I want to stress the Ancient hybrid flow map in my article above already included that thin arrow of Denisovan gene flow into Europe for a very good reason – quoted.

Thanks for discussing our previous work “Rare Haplotypes in the Korean Population” which we presented at the ASHG2012 in your post “Expanding Hybrids And The Rise Of Our Genetic Common Denominator”. We appreciate your comments and hypotheses which were inspiring and helpful for our follow up research. We would like to bring your attention to our preprint in BioRxiv “Sharing of Very Short IBD Segments between Humans, Neandertals, and Denisovans” (http://biorxiv.org/content/early/2014/04/07/003988 ), where we extended and refined the analysis and included the high coverage genome sequence of the Neandertal. In particular we now included length analysis of the IBD segments which gives new insights into the timeline of admixture and introgression events. We would very much appreciate your comments and further inputs.

Thanks!
Sorting out table 1 with respect to (also previous) continental proportions:‘Only 9,003 and 4,793 IBD segments are shared by Europeans and Asians, respectively. 558 IBD segments are exclusively found in Europeans and 1,452 exclusively in Asians.’
At least, in table 1 ‘population pairs’ I still recognize the considerable share between Africa and Europe I blogged about.

First of all, I think your previous results described in “Rare Haplotypes in the Korean Population” (2012) and “HapFABIA: Identification of very short segments of identity by descent characterized by rare variants in large sequencing data” (2013) may not have received due attention or assessment yet. Hence my effort to first try to validate my blogged results (the inflated portion of European-African shared DNA snippets) by translating the dataset of the preprint back to the African-European-Asian triangle, by excluding the AMR component again.
I found the accumulated European contribution as compared to the Asian contribution, corrected for in this publication, to be even more extreme (8,6% versus 4,6%) than in previous publications (2012: 8,4% versus 6,1%; 2013: 11,8% versus 6,8%). While it goes without saying that Asians should have more archaic DNA than Europeans! Reluctance to consider this shared European-African portion as essentially European seems to be the logical consequence of embracing Out of Africa. However, the African tendency for smaller IBD segments being noted in the article, doesn’t seem to involve the shared European-African portion in any significant way! Figure 8 (2013) reveals that the distribution of IBD segment length does not differ so much between Asian and European samples, as compared with on average shorter African samples – except for a second peak for the Asian sample that might indicate an additional, more recent Asian admixture event. Nevertheless, the second “Asian” peak, though small in figure 8 (2013), may indeed be the true cause of the Asian excess of archaic DNA, apparently without this having significantly altered the total number of Asian IBD segments.